Current technology for the intraocular introduction of drugs consists of either bulky, implantable drug delivery devices or injectable microspheres which contain drugs. These delivery systems suffer from drawbacks which make them undesirable for general clinical use. In particular, implantation of bulky ocular implants requires surgery, with all its attendant risks. Microspheres suffer from the drawback that they migrate within the eye, either into the visual axis, or into adjacent tissue sites.
Some patents which exemplify the current state of this technology, none of which have been developed into clinically useful devices, are discussed below. In order to discuss these devices, it is necessary to clarify some terms which are used in these patents.
The literature uses the term "ocular" in a confusing manner, improperly categorizing intraocular devices with extra-ocular devices. "Ocular" should be referenced using these terms which reflect anatomy, physiology and the invasiveness of the particular method.
As used in this application, "extraocular" refers to the ocular surface and the (external) space between the eyeball and the eyelid. Example of "extraocular" regions include the eyelid fornix or cul-de-sac, the conjunctival surface and the corneal surface. This location is external to all ocular tissue and an invasive procedure is not required to access this region. Extraocular devices are generally easily removable, even by the patient. Examples of extraocular systems include contact lenses and "topically" applied drops.
The following patents disclose extraocular systems which are used to administer drugs to the extraocular regions.
Higuchi et al. discloses in U.S. Pat. Nos. 3,981,303, 3,986,510 and 3,995,635, a biodegradable ocular insert which contains a drug. The insert can be made in three different shapes for retention in the cul-de-sac of the eyeball, the extraocular space between the eyeball and the eyelid. Several common biocompatible polymers are disclosed as suitable for use in fabricating this device. These polymers include zinc alginate, poly (lactic acid), poly (vinyl alcohol), poly (anhydrides) and poly (glycolic acid). The patents also disclose membrane coated devices with reduced permeation to the drug and hollow chambers holding the drug formulation.
British Patent 1,529,143 discloses a crescent-shaped drug releasing ocular insert. This insert is placed and retained in the upper fornix above the upper eyelid and the eyeball. This is another extraocular device.
Hughes et al., U.S. Pat. No. 4,201,210 discloses an extraocular device for use in animal eyes. This device is a controlled release system in the shape of a ring.
Theeuwes, U.S. Pat. No. 4,217,898, discloses microporous reservoirs which are used for controlled drug delivery. These devices are placed extraocularly in the ocular cul-de-sac. Four device shapes are disclosed. Among the polymer systems of interest include poly (vinylchloride)-co-poly (vinyl acetate) copolymers.
Kaufman discloses in U.S. Pat. Nos. 4,865,846 and 4,882,150 discloses an ophthalmic drug delivery system which contains at least one bio-erodible material or ointment carrier for the conjunctival sac. Suitable drugs which are used in this delivery system include pilocarpine. The patent discloses polymer systems, such as, poly (lactide), poly (glycolide), poly (vinyl alcohol) and cross linked collagen, as suitable delivery systems.
Brightman et al., U.S. Pat. No. 4,474,751, discloses a biodegradable ocular insert for the controlled delivery of ophthalmic material. This insert is an extraocular insert which is attachable to the third eyelid in animal eyes. The insert is used for the controlled delivery of medication.
The preceding patents all relate to extraocular systems, as the term is defined above.
Intraocular systems are those systems which are suitable for use in any tissue compartment within, between or around the tissue layers of the eye itself. These locations include subconjunctival (under the ocular mucous membrane adjacent to the eyeball), orbital (behind the eyeball), and intracameral (within the chambers of the eyeball itself). In contrast to extraocular systems, a surgical procedure consisting of injection or implantation is required to access these regions. This requires a direct invasion of the integrity of the eye during implantation, and would require major surgery to remove. The following patents disclose intraocular devices.
Wong, U.S. Pat. No. 4,853,224, discloses microencapsulated drugs for introduction into the chamber of the eye. Polymers which are used in this system include polyesters and polyethers. Examples of drugs which can be delivered by this system include 5-fluorouracil, pilocarpine and acyclovir.
Lee, U.S. Pat. No. 4,863,457, discloses a biodegradable device which is surgically implanted intraocularly for the sustained release of therapeutic agents. The device is designed for surgical implantation under the conjunctiva (mucous membrane of the eyeball). The device is disc-shaped with a protruding "handle" for suture fixation.
Krezancaki, U.S. Pat. No. 4,188,373, discloses a pharmaceutical vehicle which gels at human body temperature. This vehicle is an aqueous suspension of the drug and gums or cellulose derived synthetic derivatives. The suspension remains liquid below 30.degree. C. (room temperature), and only undergoes a sol-gel transformation in the temperature range 25.degree.-40.degree. C. Thus, in this system, a covalent chemical interaction is taking place within the site of injection.
Haslam et al. discloses in U.S. Pat. Nos. 4,474,751 and 4,474,752 a polymer-drug system which is liquid at room temperature and gels at body temperature. Suitable polymers used in this system include polyoxyethylene and polyoxy propylene. Suitable drugs include 5-FU, gentamycin, triamcinolone, and acyclovir. This system requires an intraocular, temperature dependent chemical polymerization reaction between the polymer components. This is fundamentally different from the concept of the present invention. U.S. Pat. No. 4,474,753 discloses the use of this system in a topical setting.